Role of Sphingolipids in Cardiac Ischemia

描述（由申请人提供）：急性心肌缺血，如心肌梗死（MI）是美国的主要死亡原因之一。到目前为止，还没有FDA批准的药物通过直接干扰细胞死亡过程来减少梗死面积或防止进展为MI。大多数治疗涉及医学（例如，TPA）或程序性（例如，血管成形术）旨在再灌注缺血心肌的治疗。有证据表明，细胞死亡过程中的一个非常早期的事件涉及鞘脂信号分子的激活，这在很大程度上损害了心脏细胞。本SBIR的I期和II期工作的目标是证明中性鞘磷脂酶（nSMase）及其接头蛋白FAN（中性SMase激活相关因子）是心肌缺血患者心脏保护治疗的有效靶点，这些信号成分位于死亡过程中MAP激酶、半胱天冬酶和原癌基因的上游。除了验证的目标，我们打算阐明的作用机制的关键鞘脂信号分子在产生负性肌力和细胞死亡与急性心肌缺血。在第一阶段的工作中，我们打算通过手术在缺乏鞘脂信号系统这些重要成分的FAN和nSMase敲除小鼠中产生可逆的心肌梗死。在该缺血/再灌注（IR）损伤模型中，如果与对照组相比，KO小鼠中FAN/nSMase信号传导系统无功能，则梗死面积占风险面积的百分比预计会降低。这些方法将与我们的IR损伤的心肌细胞培养模型结合使用，为FAN/SMase信号系统是急性心肌缺血的关键致病因素提供额外的原理证明

DESCRIPTION (provided by applicant): Acute cardiac ischemia such as myocardial infarction (MI) is one of the leading causes of death in the US. To date, there are no FDA-approved drugs that reduce the size of the infarct or prevent the progression to MI by directly interfering with the cell death process. Most treatments involve either medical (e.g., TPA) or procedural (e.g., angioplasty) treatments intended to reperfuse the ischemic myocardium. Evidence suggets that a very early event in the cell death process involves activation of sphingolipid signaling molecules that are largely damaging to cardiac cells. It is the goal of the proposed work in both Phase I and Phase II of this SBIR is to prove the principle that the neutral form of sphingomyelinase (nSMase) and its adaptor protein, FAN (factor associated with neutral SMase activation), are valid targets for cardioprotective therapy in patients with myocardial ischemia.These signaling components are up-stream of the MAP kinases, caspases and proto-onogenes of the death process. In addition to validating the targets, we intend to elucidate the mechanisms of action of key sphingolipid signaling molecules in producing the negative inotropy and cell death associated with acute cardiac ischemia. In Phase I of the work, we intend to surgically produce reversible cardiac infarcts in FAN and nSMase knockout mice lacking these important components of the sphingolipid signaling system. In this model of ischemia/reperfusion (IR) injury, infarct sizes as a percentage of areas of risk are expected to be reduced if the FAN/nSMase signaling system is non-functional in the KO mouse compared to control litermates. These methods will be used in conjunction with our cardiomyocyte cell culture model of IR injury provide additional proof-of-principle that the FAN/SMase signaling system is key causal factor in acute cardiac ischemia